Biological receptors are linear polymers of either amino acids or nucleotides that are folded to create three-dimensional envelopes for substrate binding. The specific three-dimensional arrangements of these linear arrays, and the placement of charged sites on the envelope surface are the products of evolutionary selection on the basis of functional efficacy. Biological receptors including antibodies, enzymes, ribozymes and transport proteins to mention just a few bind selectively to specific sets of compounds and the stereospecific and selective interactions between the relevant molecular species forms the basis of antibody-antigen interactions, biological toxicity and drug design. Although non-specific binding occurs, the functionality of receptors is generally dependent on their capacity to bind with high affinity to a limited set of substrates. For example, the immune system of vertebrates relies on the ability of antibodies to bind to a specific set of antigens.
The selectivity of biological receptors depends upon differences in the strength of attractive and repulsive forces generated between the receptor and the substrate. The magnitude of these forces varies in part with the magnitude and proximity of charged sites on the receptor and substrate surfaces. Charge sites can be formed by ionization of the substrate due to the addition or removal of electrons. Charge sites also arise in neutral, polar molecules due to asymmetrical sharing of electrons in covalent bonds. Electronegative atoms acquire partial negative charges by displacement of electrons away from less electronegative atoms. The resulting charge asymmetry generates a local or atomic dipole moment. Charge sites can also be induced when an uncharged molecule is brought into close proximity with a charged site on the receptor surface. Under these conditions a partial displacement of the electron orbitals in the portion of the substrate close to the charge site on the receptor may induce a net local charge. The strength of these induced charges varies with the susceptibility of the electrons in the affected portion of the substrate to displacement (polarizability), as well as the strength and proximity of the charged site on the receptor.
Because substrates differ in the number and magnitude of the charged sites present or induced on their surfaces, as well as the spatial arrangement of these sites, binding affinity can vary with substrate structure. Substrates with similar binding affinities for the same receptor have a high likelihood of sharing a common spatial arrangement of at least some of their induced and fixed charged sites. If the function of the receptor is correlated with binding affinity, then substrates with similar binding affinities will also be functionally similar in their effects. It is in this sense the receptor can be said to recognize or quantify similarities between the substrates.
Recent advances in molecular theory have made numerous contributions to the design of drugs, pesticides and polymers. Molecular theory provides tools based on quantum chemical techniques and a variety of methods that make use of molecular dynamics and Monte Carlo simulations based on empirical potential energy functions. These methods are applied to the determination of the geometric and electronic structural properties of bioactive molecules and polymers. Two principal concerns in the development of these methods are the electronic characteristics (e.g. charge-distribution, dipole and quadrapole moments and molecular electrostatic potential) and the nature of the active or functional conformation of a molecule.
A significant computational tool in this field is high-resolution force-field simulation based on data from simple experimental systems or ab initio quantum mechanical calculations. Similar approaches can be used to generate models of the distribution of charges over a molecular surface. Such quantum chemical approaches can be applied to a wide variety of small molecules. However, these methods are limited by the significant number of torsional degrees of freedom and corresponding conformational complexity of large molecules.
An important focus of these studies is the description of stereospecific and selective interactions between two molecular species, including antigens and antibodies or pharmacophores and target proteins. Such analyses at the level of individual molecules can be critical steps in the design of novel compounds with specific properties or functions. Descriptions of molecular interactions can be made by empirical description of the participating molecular species, for example by NMR or X-ray crystallography. Alternatively, one or both of the participating molecules may be modeled by a chemical or computational surrogate or model. Antibodies generated for various pharmacophores and toxophores are used as structural models of the active sites of their targets. Phage display of antibody proteins can also be used to develop structural models of receptors and the identification of selective ribozymes generated by combinatorial techniques represents a similar approach to the indirect description of biological target sites.
The structures of many protein receptor molecules have been determined by x-ray crystallography and NMR. This data is the basis for structure-based design of novel pharmaceutical agents (Kuntz, I. D. et al. (1982) J. Mol. Biol. 161: 269). When the proposed target protein cannot be identified or characterized directly, alternative computational techniques, including homology modelling (Blundell, T. L. et al. (1987) Nature, 326: 347), pharmacophore mapping (Martin, Y. C. et al. (1993) J. Comput.-Aided Design 7: 83) and comparative molecular field analysis (ComFA) (Cramer, R. D. et al. (1988) J. Am. Chem. Soc. 110: 5959) have been used to design pharmacophores that can interact with the receptor.
Traditional methods used in molecular recognition to identify or discover novel chemical compounds or substrates for selective binding affinity to receptors are based on finding molecular common subgraphs of active substrates and using these to predict new, similar compounds. A drawback to this technique is that it presupposes substrates exhibiting a similar efficacy for binding are structurally similar. In many cases however structurally dissimilar substrates can exhibit similar binding affinities for the same receptor. More current techniques based on quantitative structure-activity relationships (QSAR) are suited only to developing novel compounds within the same structural class and is largely inadequate at developing new molecular structures exhibiting the desired selective affinity, see for example Dean, Philip M., "Molecular Recognition: The Measurement and Search For Molecular Similarity in Ligand-Receptor Interaction", in Concepts and Applications of Molecular Similarity, Ed. Mark A. Johnson and Gerald M. Maggiora, pp. 211-238 (1990).
Recent efforts have been directed at the construction of atomic models of either pseudoreceptors, in which atoms and functional groups are connected, or minireceptors, comprised of unconnected sets of atoms or functional groups (Snyder, J. P. (1993) In 3D QSAR in Drug Design: Theory, Methods and Applications; Kubinyi, H. Ed.; Escom, Leiden. P. 336). Related methods involve surrounding known target ligands with a number of model atoms and calculation of the intermolecular forces generated between the ligand and the receptor model. Such models have a high correlation between calculated binding energy and biological activity (Walters, D. E. and Hinds, R. M. (1994) J. Medic. Chem. 37: 2527) but have not been developed to the point where novel chemical structures exhibiting selective affinity for the receptor models can be produced.
Therefore, it would be very advantageous to provide a method for identifying non-trivial similarities between different chemical structures which are both sufficient and necessary to account for their shared properties which can then be used as the basis for the design of new chemical structures with useful functional properties based on specific combinations of steric configuration and binding affinity.